Low-Dose Glucagon to Prevent and Treat Exercise-Associated Hypoglycemia in Individuals With Type 1 Diabetes: A Systematic Review and Meta-analysis

OBJECTIVE People with type 1 diabetes (T1D) struggle to manage exercise because of hypoglycemia risk. RESEARCH DESIGN AND METHODS This systematic review and meta-analysis evaluated low-dose glucagon's efficacy for preventing and treating exercise-induced hypoglycemia in T1D. Medline, Embase, and Cochrane CENTRAL were searched for randomized controlled trials and crossover studies until September 2024. The analysis included T1D adolescents and adults treated with low-dose glucagon versus nonglucagon treatments. Studies with glucagon-like peptides, noninsulin combinations, or uncontrolled exercise settings were excluded. Two authors extracted the data. The methodological quality was assessed with the Risk of Bias-2 tool and Grading of Recommendations Assessment, Development and Evaluations framework. Risk of Bias 2 informed a sensitivity analysis. The meta-analysis employed a random effects model to estimate the pooled treatment effects on hypoglycemia and time below range (TBR) (glucose <3.9 mmol/L), as well as secondary outcomes and adverse effects. RESULTS Of 6,792 records, 12 studies involving 248 individuals (mean age: 36 ± 10.5 years) met inclusion criteria. The meta-analysis showed significant reductions in hypoglycemia risk (risk ratio 0.54; 95% CI 0.35, 0.84) and TBR (−3.91 percentage points; 95% CI −6.27, 1.54) with low-dose glucagon. Sensitivity analysis yielded a slightly more confident effect size for hypoglycemia and TBR. However, overall adverse events increased with low-dose glucagon (risk ratio 2.75; 95% CI 1.07, 7.08). The included studies were few and heterogeneous, which may have influenced the overall outcomes. CONCLUSIONS Low-dose glucagon reduces exercise-induced hypoglycemia and TBR in T1D individuals. Future research should optimize glucagon dosage and timing for various exercise types and durations to confirm real-world effectiveness.